Cancer immunotherapy is a new therapy that inhibits or kills cancer cell by activating the human immune system and enhancing the antitumor immunity of oneself. This method has made breakthroughs after more than 100 years of hard work. In 2013, Science ranked tumor immunotherapy as the winner of the Top 10 scientific breakthroughs of this year (Couzin-Frankel J., 2013, Science, 342: 1432-1433). Tumor immunotherapy has become one of the most promising fields of antitumor therapy. This therapy mainly includes immune checkpoint inhibitor and cell therapy. In recent years, immune checkpoint inhibitor is a popular research topic in the field, which has made a significant clinical research progress, providing a new weapon for combating cancer (Sharma P, Allison J. P., 2015, Science, 348: 56-61).
Compared with normal cells, tumor cells have many genetic and epigenetic changes. Immune system can use the surface antigens produced by tumor cells to distinguish the two, thereby triggering the antitumor immune response. In the process of T cell antitumor immunity, after the T cell is activated by the T cell receptor (TCR)-mediated antigen recognition signal, T cell effect is comprehensively regulated through costimulatory signals and coinhibitory signals. These signals are called immune checkpoint, including inhibitory receptors that inhibits the signals such as cytotoxic T-lymphocyte associated antigen 4 (CTLA4), programmed death protein 1 (PD-1), V-domain immunoglobulin suppressor of T-cell activation (VISTA), T cell immunoglobulin and mucin domain-containing-3 (TIM3), lymphocyte activation gene 3 (LAG3), etc., and activating receptors that stimulates the signals such as CD28, CD134 (OX40), glucocorticoid-induced TNFR-related protein (GITR), CD137, CD27, HVEM, etc. (reference is made to FIG. 1) (Mellman I., Coukos G., Dranoff G., 2011, Nature, 480: 480-489). Under normal physiological conditions, the immune checkpoints on one hand participate in maintaining immune tolerance of the autoantigen to avoid autoimmune disease; and on the other hand avoid tissue injury caused by excessive activation of immune response. However, the tumor cells may evade immune killing by immune checkpoints inhibiting T cell activation. Therefore, it is necessary to reactivate T cells to attack tumor cells by activating the costimulatory signals (step on “accelerator”) and inhibiting the coinhibitory signals (loose “brake”), thereby realizing tumor immunotherapy. Clinical researches show that immune checkpoint blockade is one of the key strategies of T cell activation, and the successful listing of several antibody drugs and huge market potential have undoubtedly made the research of immune checkpoints the focus of major pharmaceutical companies at home and abroad (Pardoll D. M., 2012, Nat. Rev. Cancer., 12: 252-264). At present, PD-1 is one of the most popular immune checkpoints.
PD-1 is expressed in activated T cell, B cell, and bone marrow cell, and belongs to CD28 family. It is a type 1 transmembrane glycoprotein on T cell and is consisted of 288 amino acids. PD-1 has a molecular structure consisting of an immunoglobulin IgV-like (amino acid 35-145) extracellular domain, a transmembrane domain and a cytoplasmic tail region having a function of connecting signal peptide, wherein the extracellular domain binds to the ligand to play an important function (Cheng X., Veverka V, Radhakrishnan A., et al. 2013, J. Biol. Chem., 288: 11771-11785). The ligand of D-1 includes two types, programmed death protein ligand 1 (PD-L1) and programmed death protein ligand 2 (PD-L2), wherein PD-L1 is constitutively expressed on a variety of cancer cells, T cells, APC and a variety of non-hematopoietic cells; and PD-L2 is restrictively expressed only in dendritic cells and macrophages. PD-L1/2 belongs to B7 family, and is type 1 transmembrane glycoproteins. PD-L1 is consisted of 290 amino acids; and PD-L2 is consisted of 262 amino acids. The molecular structures of PD-L1/2 are all consisted of an immunoglobulin IgV-like domain (distal end of the membrane), an IgC-like domain (proximal end of the membrane), a transmembrane domain and a short and conserved cytoplasmic domain (Lázár-Molnár E., Yan Q., Cao E., et al. 2008, Proc. Natl. Acad. Sci. USA., 105: 10483-10488). Isothermal titration calorimetry (ITC) experiments show that the interaction between PD-1 and PD-L1 is derived by entropy change, and the interaction between PD-1 and PD-L2 is derived by enthalpy change. The two competitively bind with the PD-1, and the affinity between PD-L2 and PD-1 is 3-4 times that of PD-L1 and PD-1. This weak interaction may be the key to triggering the latent inhibition signal (Ghiotto M., Gauthier L., Serriari N., et al. 2010, Int. Immunol., 22: 651-660). The interaction between PD-1 and its ligand inhibits T cell activation, which is essential for maintaining normal immune tolerance in the body. In tumor cells and when the virus is infected, PD-1 on T cells is induced to high expression and the expression of PD-L1/2 is up-regulated, resulting in continuous activation of PD-1 signaling pathway and inhibition of T cell proliferation (see FIG. 2), and resulting in immune escape of tumor cells and pathogens (Fuller M. J., Callendret B., Zhu B., et al. 2013, Proc. Natl. Acad. Sci. USA., 110: 15001-15006; Dolan D. E., Gupta S., 2014, Cancer Control, 21: 231-237; Chen L., Han X., 2015, J. Clin. Invest., 125: 3384-3391; Postow M. A., Callahan M. K., Wolchok J. D., 2015, J. Clin. Oncol., 33: 1974-1982).
Currently, three antibody drugs that block this signaling pathway have been approved by the FDA, and multiple antibody drugs worldwide are in clinical research (see Table 1) (Li Y, Li F., Jiang F., et al. 2016, Int. J. Mol. Sci., 17: E1151). Several studies have confirmed that these antibody drugs are effective in a variety of tumors, such as melanoma, non-small cell lung cancer, renal cell carcinoma, ovarian cancer, bladder cancer, stomach cancer, head and neck and esophageal squamous cell carcinoma, and Hodgkin's lymphoma.
TABLE 1List of approval and clinical research of target PD-1 and PD-L1 antibody drugs worldwideTargetActive compoundDeveloperTypeClinical statusPD-1NivolumabBristol-Myers Squibbhuman IgG4FDA approval: recurrent unresectable melanoma,metastatic non-small cell lung cancer (NSCLC) anda dvanced renal cell carcinomaPembrolizumabMerckhuman IgG4FDA approval: recurrent unresectable melanoma,metastatic NSCLC that expresses PD-L1AMP-224AmplimmunePD-L2 IgG2a fusionPH 1proteinAMP-514AmplimmunePD-L2 fusion proteinPH 1-2REGN2810Regeneronhuman IgG4PH 1PDR001Novartis—PH 1-2BMS-936559Bristol-Myers Squibbhuman IgG4PH 1-2BGB-A317BeiGenehuman IgG4PH 1 (U.S.A.)JS001-PD-1Shanghai Junshi—PH 1 (China)SHR-1210Shanghai Hengrui—PH 1 (China)PD-L1MPDL3280ARochehuman IgG1kFDA approval: bladder epithelial carcinoma,metastatic NSCLCMEDI4736MedImunne/AstraZenecahuman IgG1kPH 1-3MSB0010718CMerck Seronohuman IgG1PH 1-3
In view of above, significant progresses have been made in the immune checkpoint inhibitors targeting PD-1/PD-L1 antibody drugs. However, the conventional antibody drugs are required to be administered by injection, have various ADMET problems (drug absorption, distribution, metabolism, excretion and toxicity), or have serious side effects associated with the immune system, etc., which may be due to the too long half-lives of these macromolecules (as long as 15-20 days), causing the target to be continuously inhibited. Compared with conventional antibody drugs, small molecule immune checkpoint inhibitors have obvious advantages, including oral administration is feasible, and side effects are decreased to the utmost extent by regulating the pharmaceutical properties. In addition, small molecule inhibitors will have lower cost and price advantages. To date, in addition to the oral small molecule inhibitors CA-170 (targeting PD-L1/VISTA, Phase I clinical study, U.S.A.) and AUPM-327 (targeting PD-L1/TIM3, preclinical study) reported by Aurigene and Curis, no small molecule inhibitor has been publicly reported.
The small molecular immune checkpoint inhibitors disclosed in the present disclosure may be used for treating and/or preventing melanoma, non-small cell lung cancer, renal cell carcinoma, ovarian cancer, bladder cancer, stomach cancer, head and neck and esophageal squamous cell carcinoma, and Hodgkin's lymphoma, etc., but not limited to this. At the same time, these compounds or the pharmaceutical compositions containing them as active ingredient may maximize the clinical efficacy of these diseases in a safe therapeutic window.